A transformation in the mechanism by which the urokinase receptor signals provides a selection advantage for estrogen receptor-expressing breast cancer cells in the absence of estrogen

作者：Eastman Boryana M; Jo Minji; Webb Drue L; Takimoto Shinako; Gonias Steven L^*

来源：Cellular Signalling, 2012, 24(9): 1847-1855.

DOI：10.1016/j.cellsig.2012.05.011

• Urokinase-type plasminogen activator
• uPAR
• ERK
• EGF receptor
• Estrogen receptor
• Breast cancer

Binding of urokinase-type plasminogen activator (uPA) to its receptor, uPAR, in estrogen receptor-alpha (ER alpha) expressing breast cancer cells, transiently activates ERK downstream of FAK, Src family kinases, and H-Ras. Herein, we show that when uPAR is over-expressed, in two separate ER alpha-positive breast cancer cell lines, ERK activation occurs autonomously of uPA and is sustained. Autonomous ERK activation by OAR requires H-Ras and Rac1. A mutated form of uPAR, which does not bind vitronectin (uPAR-W32A), failed to induce autonomous ERK activation. Expression of human uPAR or mouse uPAR but not uPAR-W32A in MCF-7 cells provided a selection advantage when these cells were deprived of estrogen in cell culture for two weeks. Similarly, MCF-7 cells that express mouse uPAR formed xenografts in SOD mice that survived and increased in volume in the absence of estrogen supplementation, probably reflecting the pro-survival activity of phospho-ERK. Autonomous uPAR signaling to ERK was sensitive to the EGFR tyrosine kinase inhibitors, Erlotinib and Gefitinib. The transition in uPAR signaling from uPA-dependent and transient to autonomous and sustained is reminiscent of the transformation in ErbB2/HER2 signaling observed when this gene is amplified in breast cancer. uPAR over-expression may provide a pathway for escape of breast cancer cells from ER alpha-targeting therapeutics.

• 出版日期2012-9